1. Field of the Invention
The present invention relates to a novel composition for preventing or treating hepatitis C virus capable of effectively inhibiting replication of virus by regulating stability and activity of kinase involved in phosphorylation of replicase of hepatitis C virus.
2. Discussion of Related Art
Hepatitis C virus (HCV) is the major etiologic agents of non-A and non-B hepatitis. More than 170 million people worldwide are chronically infected with HCV. Persistent HCV infection establishes a chronic hepatitis that can lead to liver cirrhosis and hepatocellular carcinoma. Further, the combined administration of IFN-α injection with ribavirin currently used as the standard HCV therapy is limited in use due to its serious side effects. Furthermore, IFN-α is effective in less than about 50% of genotype 1 HCV-infected patients. Therefore, various therapeutic options have been under investigation in order to develop effective and specific therapies with the least toxicity.
The HCV has a positive-sense single stranded RNA genome of approximately 9.6 kb, which consists of one long open reading frame (ORF) flanked by untranslated regions (UTRs) at both the 5′ and 3′ ends of the genome. The ORF encodes a single polyprotein that is proteolytically processed by cellular and viral proteases into at least 10 functional viral proteins, including both structural and nonstuructural proteins. A HCV NS5B protein of 65 kDa, responsible for RdRp (RNA-dependent RNA polymerase) activity, is the key enzyme essential for HCV RNA replication.
According to preceding research, it was found that viral RNA polymerase is phosphorylated by PRK2 (protein kinase C-related kinase 2) and inhibition of PRK2 activity by a PRK2 inhibitor leads to effective inhibition of HCV replication.
Meanwhile, heat shock protein 90 (Hsp90) protects various cellular client proteins from proteasomal degradation through interactions with the cellular client proteins and also exhibits additional functions. The Hsp90 was identified as a host factor essential for maturation of viral protein. Recently, it was proved that the Hsp90 forms a trimeric complex with HCV NS5A and FKBP9, a cyclophilin family immunophilin, to regulate HCV RNA replication. Furthermore, it was found that as Hsp90 inhibitors, 17-AAG (17-allyaminogeldanamycin) and 17-DMAG (17-(dimethylaminoethylamino)-17-demethoxygeldanamycin), which are analogues of geldanamycin as a benzoquinone ansamycin antibiotic, inhibit HCV replication in cellular-based assays using HCV replicons and in HCV-infected chimeric mice with trans-humanized liver. However, a precise role of the Hsp90 in HCV replication remains unknown. The Hsp90 helps folding of various client proteins. One of its putative clients is PDK1 (3-phosphoinositide-dependent kinase-1). However, destabilization of the PDK1 was not observed in breast cancer lines, suggesting a cell-type dependent differential regulation of the PDK1 stability by Hsp90 inhibition.
It was proved by the present inventors that the PDK1 is an upstream kinase of PRK2 and the PRK2 is a cellular kinase responsible for HCV NS5B phosphorylation. Thus, the present inventors completed the present invention by analyzing whether Hsp90 inhibition leads to an inhibitory effect on HCV replication by affecting the phosphorylation of the NS5B protein.